Let’s start with serum ferritin, an iron containing protein that’s considered the most sensitive and specific noninvasive diagnostic test for evaluating total body iron stores (vs. the gold standard—but invasive— iron staining of bone marrow). ¹

Although the optimal ferritin threshold to diagnose iron deficiency (ID) varies, compared to bone marrow iron reserves, levels below 15 ug/L are considered 98% specific and 78% sensitive.² At a higher cut off of less than 45 ug/L, its sensitivity is 85% with a specificity of 92%.³ So if your patient’s ferritin level is less than 45 ug/L—especially less than 15 ug/L—you can be quite confident that they have ID.  

Argument is often made that ferritin levels may be misleadingly high even in the presence of ID because it is an acute phase reactant and its synthesis is expected to increase in a variety of infectious and non-infectious inflammatory conditions. But this argument can only be taken so far, because ferritin synthesis still depends on the presence of cellular iron, such that even in the presence of inflammation, its levels are unlikely to be more 100 ug/L in patients with low iron stores or “absolute ID”.

Absolute ID should be distinguished from “functional” ID which is associated with adequate iron stores but inadequate iron availability to tissues due to cytokine-mediated hepcidin production and macrophage sequestration of iron. ⁴

This brings us to another key protein, serum transferrin which transports iron to vital tissues, including the bone marrow.  Transferrin saturation (TSat) is not only low (≤20%) in absolute ID but also in functional ID. ¹ This is where a combination of serum ferritin and TSat is helpful. A low TSat combined with a normal or high serum ferritin suggests functional ID with the previously discussed caveat that serum ferritin levels may be normal or elevated—but usually less than 100 ug/L)— in patients with absolute ID and concurrent inflammation.

So in your patient with anemia, after reviewing their serum ferritin and TSat, you should have a good idea of whether they have ID and, if so, whether it’s related to an absolute or functional ID. In another post, I will discuss guidelines on the diagnosis and treatment of functional ID.

Bonus Pearl: Did you know that the commonly-cited difference in the threshold for anemia in males vs females (<13.0 g/dL and <12 g/dL, respectively) by WHO may at least in part be related to unrecognized and untreated ID in the female population studies over 50 years ago? ¹

Liked this post? Download the app on your smart phone and sign up below to catch future pearls right into your inbox, all for free!

References

1. Martens KL, DeLoughery TG. Iron deficiency anemia. Ann Intern Med 2026; 179:1-16. Iron Deficiency Anemia | Annals of Internal Medicine
2. Hallberg L, Bengtsson C, Lapidus L, et al. Screening for iron deficiency: an analysis based on bone marrow examinations and serum ferritin determinations in a population sample of women. Br. J Haematol 199385:787-798. Screening for iron deficiency: an analysis based on bone-marrow examinations and serum ferritin determinations in a population sample of women. – Abstract – Europe PMC
3. Rockey DC, Altayar O, Falck-Ytter Y, et al. AGA technical review on gastrointestinal evaluation of iron deficiency. Gastroenterology 2020;159:1097-1119. AGA Technical Review on Gastrointestinal Evaluation of Iron Deficiency Anemia – Gastroenterology
4. Camaschella C, Girelli D. The changing landscape of iron deficiency. Mol Aspects Med 2020;75:100861. The changing landscape of iron deficiency – PubMed

Disclosures/Disclaimers: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!